46. Investigating a Genetic Disorder of Childhood

Question 1

What is the role of a clinical geneticist?

Describe the breadth of genetic conditions.

Answer 1

Disgnosis of genetic disorders, investigation and genetic risk assessment, genetic counselling, appropriate follow-up support to pt and extended family, liaison with genetic labs, eduction and training, research.

Covers prenatal (>80% activity is screening for common aneuploidies) and postnatal (cytogenetics in malignancy (e.g. karyotype, aneuploidy, solid tumors, haematological malignancy), genetic risk factors, molecular testing for a large number of rare single gene disorders (e.g. sickle cell, CF, breast cancer, haemochromatosis, factor V leiden).

Question 2

Describe the different types of genetic markers that can be used in analysis of genetic conditions, and how they are detected.

How are genetic markers used in linkage analysis?

What 3 ways may disease genes be identified?

Answer 2

Marker: tags a piece of DNA and can be usd to track genes in families or populations. SNP (single nucleotide polymorphism) or STR (short tandem repeat, microsatellite, highly variable length).

STRs typed across the genome in 2 families, linked markers are physically close, they mostly stay together through meiosis but can cross over in recombination. They can be used to track the location of a disaese gene.

1) Postional candidates: ID’d through genome wide genetic linkage analysis e.g. genes causing Fanconi anaemia. 2) Functional candidates: ID’d by functional association with previously ID’d disease genes. 3) Exome sequencing: ID’d as having rare variants in multiple unrelated affected individuals - an allelic series, e.g. Freeman-Sheldon syndrome.

Question 3

How could you establish whether a mutation is pathogenic?

What is the impact on families of a genetic disorder?

Answer 3

Classify genetic variants on a scale of 1-5 (1 = benign and 5 = pathogenic), but often they are 3 = variant of unknown significance. Thus approaches: searching medical literature/databases (e.g. exome aggregation consortium) or using in-silico tools to predict severity of variant.

Diagnosis: confirmation/clarification, pre-symptomatic, monitoring, donor search, inheritance pattern, carrier testing, prenatal, preimplantation, genetic counselling. Tx: tailor tx: appropriate drugs, storing cells, rational drug design, gene therapy. Wider pathology: mutations in pts with idiopathic disease.

Can take family history and present results as informative pedigree.